Human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) represents a major chronic health problem in the US and abroad. Magnetic Resonance Imaging (MRI) studies have consistently shown brain gray and white matter abnormalities and cognitive deficits in patients with HAND. Advances in treatment of HAND have been made by delivering drugs or viral vectors that can increase brain derived neurotrophic factor (BDNF) levels in the brain indirectly. BDNF promotes neuroregeneration and restores brain functions. However, BDNF cannot cross an intact blood brain barrier (BBB), and is unstable in the blood or when delivered orally. In Phase 2, we plan to further demonstrate the feasibility of our novel nanotechnology to reverse brain gray and white matter abnormalities associated with HAND, and successfully treat learning and memory deficits. In our Phase-1 studies, our first preclinical data showed: (i) our capabilities to successfully bioengineer novel BDNF-nanoparticles (NPs); (ii) the NPs noninvasively passed the BBB; (iii) the NPs effectively delivered BDNF to the brain, and (iv) the NPs significantly enhanced neurogenesis and synaptogenesis in GT-tg bigenic mice induced with doxycycline (dox) to overexpress a toxic HIV transactivator of transcription (tat) protein. The goal of this Phase-2 effort is therefore to more thoroughly test our hypothesis that BDNF-nanoparticles (NPs) deliver BDNF to the affected brain regions, reverse gray and white matter abnormalities in these regions, and improve learning and memory in a GT-tg mouse model of HAND. To accomplish our Phase-2 goals we plan a series of studies that will ascertain NP stability, brain and body distribution, and functionality in dox-induced GT-tg mice. As in Phase 1, mice will be tested with standard memory tests, but in larger numbers and with an improved treatment plan. Further, anatomical MRI and diffusion tensor imaging (DTI) will also be used to assess gray mater density and structural connectivity before and after NP/saline treatments. Thus, our Phase 2 results would clear the way to Phase 3. This research project will provide new noninvasive nanotechnology tools for early treatment of HAND. The new nanotechnology may be able to enhance brain gray matter density, improve structural connectivity, and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses, and causing fewer side effects. The development of a stable, nontoxic nanoparticle may also provide a major new tool for research of biomarkers in HAND. This nanotechnology may serve as the basis for a next generation thernostic that can specifically target relevant brain systems, and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.